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Process for ezetimibe intermediate

a technology of ezetimibe and intermediate, which is applied in the field of process for the preparation of ezetimibe intermediate, can solve the problems of unsuitable industrial production of the process

Inactive Publication Date: 2006-06-27
HETERO DRUGS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach results in a more economical and simpler process for preparing ezetimibe intermediates with high yields, typically above 80%, making it suitable for industrial production.

Problems solved by technology

The process requires strict control of cultures and chromatographic separations, which make the process unsuitable for industrial production.

Method used

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  • Process for ezetimibe intermediate
  • Process for ezetimibe intermediate
  • Process for ezetimibe intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0030]3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone (100 gm) is dissolved in toluene (750 ml), the mixture of (−)-β-chlorodiisopinocampheylborane ((−)-DIP chloride) in heptane (545 ml, 1.5M) and toluene (750 ml) is added at 0° C. to 5° C. for 1 hour. The reaction mixture is stirred for 15 hours at 25° C. to 30° C. and 340 ml of 10% sodium chloride is then added at the same temperature. The layers are separated and the organic layer is washed with 5% sodium bicarbonate (300 ml), 1N sulfuric acid (300 ml), and 10% sodium chloride (300 ml). Then the organic layer is dried on sodium sulfate to give 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone in 96% yield.

example 2

[0031]The organic layer of 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone from example 1 is mixed with 4-fluoro-N-(4-hydroxyphenyl)methylene-benzenamine (121 gm) and cooled to −10° C. Then diisopropylethylamine (260 ml) is added to the reaction mixture for 45 minutes at −10° C. to −15° C., trimethylsilylchloride (135 ml) is added and stirred for 1 hour at −20° C. to −25° C. The reaction mixture is cooled to −30° C., TiCl4 (35 ml) is slowly added to the reaction mixture at −30° C. to −35° C. and stirred for 3 hours at the same temperature. 5% Aq. tartaric acid solution (1700 ml) is added to the reaction mixture at 0° C., stirred for 1 hour and allowed the temperature to rise to 25° C. Then 20% Aq. NaHSO3 (350 ml) solution and stirred for 2 hours at 25° C. to 30° C. The organic layer is separated and washed with 1000 ml water, concentrated to 250 ml volume and added 100 ml bistrimethylsilylacetamide. Then the reaction mixture is heated to reflux for 30 minu...

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Abstract

The invention provides a process for preparing intermediate of ezetimibe, which shows hypocholesterolemic activity. Thus 3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone is reduced with (−)-DIP chloride to obtain 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone.

Description

FIELD OF THE INVENTION[0001]The present invention is related to a simple and economical process for the preparation of ezetimibe intermediate.BACKGROUND OF THE INVENTION[0002]U.S. Pat. No. 5,767,115 discloses the hypocholesterolemic activity of hydroxy-substituted azetidinones. Processes for preparing these compounds are described in U.S. Pat. No. 5,767,115, WO 97 / 16424, WO 97 / 45406, U.S. Pat. No. 5,886,171, WO 00 / 34240, J. Med. Chem. 1998, 41(6), 973–980 and J. Org. Chem. 1999, 64(10), 3714–18.[0003]WO 00 / 34240 discloses an improved process for preparing these compounds, in particular ezetimibe, (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl) -3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone of formula I.[0004]The reaction sequence of process for preparing ezetimibe is shown in scheme A.[0005]The reduction of the ketone of the formula 3a[0006]to give alcohol of formula 2a[0007]involves the use of the reducing agent borane dimethyl sulfide in the presence of the expensive ch...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D263/04C07D205/08C07D263/22C07D277/34C07D277/36C07D291/04
CPCC07D205/08C07D263/22C07D277/36C07D277/34C07D263/26
Inventor REDDY, BANDI PARTHASARADHIRATHNAKAR REDDY, KURARAJI REDDY, RAPOLUMURALIDHARA REDDY, DASARISUBASH CHANDER REDDY, KESIREDDY
Owner HETERO DRUGS LTD
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